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J Carneiro

Publications and source records attributed to J Carneiro.

At least 19 recordsLinked to original sources
PubMed2001

Three-cell interactions in T cell-mediated suppression? A mathematical analysis of its quantitative implications.

Aiming to further our understanding of T cell-mediated suppression, we investigate the plausibility of the hypothesis that regulatory T cells suppress other T cells (target cells), while both cells are conjugated with one APC. We use a mathematical model to analyze the proliferation inhibition scored during in vitro suppression assays. This model is a radical simplification of cell culture reality, assuming that thymidine incorporation is proportional to the number of target cells that would instantaneously form conjugates with APCs that are free of regulatory cells. According to this model the inhibition index should be mainly determined by the number of regulatory cells per APC and should be insensitive to the number of target cells. We reanalyzed several published data sets, confirming this expectation. Furthermore, we demonstrate that the instantaneous inhibition index has an absolute limit as a function of the number of regulatory cells per APC. By calculating this limit we find that the model can explain the data under two non-mutually exclusive conditions. First, only approximately 15% of APCs used in the suppression assays form conjugates with T cells. Second, the growth of the regulatory cell population depends on the target cells, such that the number of regulatory cells per APC increases when they are cocultured with target cells and overcomes its limit. However, if neither of these testable conditions is fulfilled, then one could conclude that suppression in vitro does not require the formation of multicellular conjugates.

Animals↗
PubMed2000

Modelling T-cell-mediated suppression dependent on interactions in multicellular conjugates.

Tolerance to peripheral body antigens involves multiple mechanisms, namely T-cell-mediated suppression of potentially autoimmune cells. Recent in vivo and in vitro evidence indicates that regulatory T cells suppress the response of effector T cells by a mechanism that requires the simultaneous conjugation of regulatory and effector T cells with the same antigen-presenting cell (APC). Despite this strong requirement, it is not yet clear what happens while both cells are conjugated. Several hypotheses are discussed in the literature. Suppression may result from simple competition of regulatory and effector cells for activation resources on the APC; regulatory T cells may deliver an inhibitory signal to effector T cells in the same conjugate; or effector T cells may acquire the regulatory phenotype during their interaction with regulatory T cells. The present article tries to further our understanding of T-cell-mediated suppression, and to narrow-down the number of candidate mechanisms. We propose the first general formalism describing the formation of multicellular conjugates of T cells and APCs. Using this formalism we derive three particular models, representing alternative mechanisms of T-cell-mediated suppression. For each model, we make phase plane and bifurcation analysis, and identify their pros and cons in terms of the relationship with the large body of experimental observations on T-cell-mediated suppression. We argue that accounting for the quantitative details of adoptive transfers of tolerance requires models with bistable regimes in which either regulatory cells or effectors cells dominate the steady state. From this analysis, we conclude that the most plausible mechanism of T-cell-mediated suppression requires that regulatory T cells actively inhibit the growth of effector T cells, and that the maintenance of the population of regulatory T cells is dependent on the effector T cells. The regulatory T cell population may depend on a growth factor produced by effector T cells and/or on a continuous differentiation of effector cells to the regulatory phenotype.

Antigen-Presenting Cells↗
PubMed2000

A mathematical analysis of TCR serial triggering and down-regulation.

Despite the increasing knowledge on the pathways involved in TCR signal transduction and T cell activation, the molecular mechanism of TCR triggering by ligand, MHC-peptide complexes, is still elusive and controversial. The present paper addresses the controversy on the early events of TCR engagement and triggering. Mathematical modelling techniques are applied to experimental data to infer plausible molecular mechanisms of TCR triggering and down-regulation. A similar approach has been followed by Bachmann et al. (Eur. J. Immunol. 1998, 28: 2571 - 2579), who concluded that the TCR triggering requires the formation of MHC-TCR dimers or trimers. We report here the failure to generalize this conclusion to the data reported by Valitutti et al. (Nature 1995, 375: 148 - 151). We show that there are several kinetic features in these experimental curves of TCR down-regulation that cannot be explained by the simple model proposed by Bachmann et al. unless some phenomenological extensions are considered. These extensions are: (1) a ligand independent turnover of the TCR; (2) a transient accumulation of triggered TCR; (3) a high order of TCR triggering kinetics; and (4) two pools of membrane TCR in dynamic equilibrium.

Animals↗
PubMed1999

Functional diversity of natural IgM.

This paper proposes a method for the quantitative characterization of repertoire diversity of an unknown mixture of antibodies on the basis of its reactivity profile in the quantitative immunoblot (QIB). The QIB is calibrated by measuring the reactivity profiles of supernatants of known 'diversity' (i.e. known numbers of B cell clones). We define a quantitative 'index of variability' (IV) which decreases regularly as the diversity increases and the profiles tend towards a common 'convergence profile'. The calibration procedure is consolidated by a mathematical model based on the Poisson distribution; this theoretical model accounts correctly for the observed convergence behavior. On the basis of this calibration curve, it is possible to estimate the diversity of an unknown antibody mixture from a measure of its IV. We conclude that the functional diversity of natural serum IgM in mice can be estimated at approximately 16,000 clones.

Animals↗
PubMed1998

Natural and induced tolerance in an immune network model.

It has been proposed that the immune system can be partitioned into central and peripheral immune systems. Recently, Carneiro et al. (1996a, b) proposed a network, model incorporating B and T lymphocytes that explicitly accounts for that partition. This model however, had some limitations that are tackled here. Two main changes were introduced: the average idiotypic connectivity is now an explicit function of time based on empirical evidence; and the activation of T lymphocytes by antigen is described by a log-bell shaped dose response curve. The new model, which also accounts for the CIS and PIS distinction, shows more reasonable results since the frequencies of tolerant, immune or autoimmune responses to an antigen are now correct. The model provides a new interpretation for tolerance induction during the neonatal period, and for the adult tolerance by low or high doses of antigen. It predicts that natural tolerance for antigens available during the neonatal period can be kept indefinitely upon their removal, while tolerance induced in the adult stages is rapidly lost upon transient removal of the antigen. A semiquantitative analysis of the model provides a simple explanation for the different results in terms of the frequency at which a limited set of canonical connectivity structures emerge during ontogenesis.

Animals↗
PubMed1998

[Prevalence of dyslipidemias in adult ambulatory laboratory tests from different health care providers].

OBJECTIVE: To detect differences in the prevalence of dyslipidemia in adult ambulatory laboratory tests from three different health care providers, in Salvador-Brazil, 1995. METHODS: The study was carried out using a probabilistic sample of 24 out of 104 laboratories (approximately equal to 25%) which performed the same enzymatic method for lipid tests with the same quality control. Laboratory tests results were separated into three groups, according to health care provider: Sistema Unico de Saúde (SUS, governamental), Health Maintenance Organizations (HMO), and Private or Patients Health Insurance (PHI). Criteria for dyslipidemias in mg/dl were: total cholesterol > or = 240; LDL-c > or = 160; HDL-c < 35 and triglycerides > or = 200. Prevalence rates, 95% confidence intervals (CI) and chi (2) test were used in the analysis. RESULTS: From the 5464 adult subjects, 14.8% were from SUS, 31.6%. from HMO and 53.6% PHI. The highest prevalence for hypercholesterolemia--28.0% (CI 24.0; 32.0) and for LDL-c > or = 160mg/dL--30.4% (CI 27.6; 33.2), were found in the HMO group. PHI had the highest prevalence for HDL-c < 35mg/dL--12.3% (CI 10.0; 13.8), and for hypertrygliceridemia--17.8% (CI 16.3; 19.3). Most of the differences among health providers were statistically significant. CONCLUSION: The best lypid profile observed in subjects from SUS suggests social differences in the prevalence of dyslipidemias. As compared to other dyslipidemias, HDL-c < 35mg/dL prevalence was lower than expected in all three groups. The data may provide insights to medical doctors and other health care professionals regarding the questions of dyslipidemias. It can also provide objective information to the patients and encourage them to change their life styles.

Adult↗
PubMed1997

Further studies on the problem of immune network modelling.

In a previous work we have analysed a family of antibody and B-cell network models (basic AB models) of the immune system. This analysis focused principally on the physiological interpretation of their parameters. Our approach consisted in building a detailed and general mathematical model (referred to as the GIB model) and then simplifying it formally to a version (named the RIB model) that belongs to the family of AB models, but which is more general than the basic AB models. From that study it was clear that some of the assumptions necessary to simplify the GIB model into the RIB one, as well as to recover the basic AB models from the RIB one, are quite unrealistic from a physiological point of view. All this raised the issue of the reliability, or even the heuristic value, of theoretical studies based on current network models for experimental immunologists. One approach to clarify this issue is to ask whether the unrealism of the assumptions implicit in the RIB and AB models entails qualitatively different behaviours between them compared to the GIB one. We initiate here such a work by performing a comparative study of a two-clone system of the AB and RIB models, and a variant of the GIB model in which the different molecular compartments were merged into a single one (labelled IGB model). Because all those models rely critically on certain B-cell activation functions, which constitute the core of an implicit model of individual B-cell reactivity or "local rules", we focused the present numerical study, to a great extent, on two parameters determining those activation functions (Hill coefficient and thresholds). Our results indicate that: (1) the RIB and IGB models display in general a much larger diversity of steady states than the AB models; (2) only under a very restricted parameter regime did all studied models behave similarly; (3) the parameter regime under which the AB and IGB models, but not the RIB one, behave similarly is still rather restricted through not as much as in (2); and (4) even relatively small quantitative changes (within reasonable values) in the postulated "local rules" can induce very large quantitative changes in the behaviour of the AB and RIB models but not the IGB model. In the light of the present results, we discuss the need of postulating a set of "local rules" solidly based on experimental evidence as a necessary condition for the reliability of current network models.

Animals↗
PubMed1997

[Prevalence of dyslipidemias in adults in laboratory tests from Salvador, Brazil].

PURPOSE: To determine the prevalence of dyslipidemia in non-hospital laboratory tests of adults from Salvador, Brazil. METHODS: The study was carried out in subjects from a probabilistic sample of 25% of a total of 104 local laboratories that used the same enzymatic method for lipid analysis with the quality control as recommended by the Brazilian Society of Clinical Analyses. These represented 93% of all non-hospital laboratories of Salvador in 1995. The odd months of 1995 were selected for sampling in the present study. Criteria for dyslipidemias were: total cholesterol > or = 240; LDL > or = 160; HDL < 35 and triglycerides > or = 200 mg/dl. Prevalence rates and their 95% confidence intervals (CI) and chi 2 test were used in the analyses. RESULTS: Tests from two of the 26 laboratories were not used in the analyses due to file problems or refusal. 7,392 adults were screened, 65% female. We observed prevalence (95% CI) of hypercholesterolemia in 30.0 (27.8; 32.2)%, high LDL in 30.1 (30.8; 35.4)% and hypertriglyceridemia in 30.4 (29.0; 31.4)% of the females. As to the male subjects, prevalences were; 24.0 (20.5; 27.5)% for hypercholesterolemia, 26.1 (22.4; 29.3)% for high LDL, 27.6 (25.7; 29.5)% for hypertriglyceridemia. All gender differences were significant. Low HDL occurred in 15.9 (14.2; 17.8)% of males and in 8.0 (7.1; 8.9)% of females. CONCLUSION: Dyslipidemia is an important risk factor observed in non-hospital laboratory tests of men and women in Salvador. Our data may provide physicians and other health care professionals with objective information to encourage life-style changes.

Adult↗
PubMed1996

A model of the immune network with B-T cell co-operation. I--Prototypical structures and dynamics.

Hitherto, "second generation" network models of the immune system have all been restricted to B-lymphocytes and the Ig molecules they produce. These models have not so far been able to provide a convincing mechanism for the distinction between a "Central Immune System" (CIS) composed of a connected network of lymphocyte clones which couple with "self" antigens in a tolerant mode, and a "Peripheral Immune System" (PIS) composed of clones with little or no supra-clonal organization and which produce classical immune responses when interacting with "non-self" antigens. Here, we present a new network model which explicitly incorporates B-T cell co-operation. In this model, B-cell activation is dependent on T-cell help, and activated T-cells are down-regulated by engagement of their TCRs by soluble Ig. We discuss the underlying biology on which we base the system of ordinary differential equations which defines the present network model. We then illustrate some basic features of the model by examining several prototypical situations with a small number of clones. Depending on the idiotypic connectivity structure, the model exhibits two distinct modes of coupling with antigens: an "immune response" mode in which T- and B-cell clones grow exponentially; and a "tolerant" mode in which T-cell clones are controlled by inclusion of all TCRs in the repertoire of an idiotypic B-cell network. Finally, we discuss the simplifying assumptions of the present model and argue that its range of validity is indeed the region of the state-space of the system where the discrimination between the CIS and the PIS take place.

B-Lymphocytes↗
PubMed1996

A model of the immune network with B-T cell co-operation. II--The simulation of ontogenesis.

This paper is based on a new model of the immune network which explicitly incorporates B-T cell co-operation. A major feature of this model is the simplifying assumption that inhibition by anti-TCR soluble Ig is the only possible down-regulatory influence on activated T-cells. This model is capable of coupling with antigens in both an "immune response" mode and a "tolerant" mode. In the present paper, we simulate the ontogenesis of the immune system by metadynamical recruitment of T- and B-cell clones from the thymus and the bone marrow, seeking to identify the conditions under which each of these modes of antigen coupling occurs. Achieving the tolerant mode depends principally on four parameters: a high value of SB, the rate of bone-marrow production of B-cells; a relatively high efficiency of T-help through mIg-TCR recognition compared with (MHC + peptide)-TCR interaction; and a relatively high value of the product PR.NA, where PR is the average probability that an Ig recognizes another molecule and NA is the number of antigens which are present throughout ontogeny. Analysis of the conditions under which these two modes can coexist, shows that this is possible when a sufficiently numerous set of founder antigens couple in a tolerant mode, whereas isolated antigens first presented once development is completed couple in an immune response mode. The present model thus provides a possible mechanism for the distinction (hitherto purely descriptive) between a Central Immune System organized as a network and responsible for tolerance, and a Peripheral Immune System responsible for immune responses.

B-Lymphocytes↗
PubMed1995

The ontogeny of class-regulation of CD4+ T lymphocyte populations.

The differential class-regulation of CD4+ T lymphocyte populations is believed to play a major role in determining the qualitative behaviour of the immune system, and in the fate of immune responses in particular. In this article we propose a model for the dynamics of the Th1 and Th2 subpopulations. We put forward the concept of an 'antigenic niche' which allows us to postulate that the key feature underlying the regulation of Th differentiation pathways is the population dynamics of the lymphocytes themselves. Using this model we are able to account for a number of well established experimental observations which were hitherto apparently unrelated and poorly understood. This suggests that our simplified model might be capturing some essential features of the immune system.

Animals↗
PubMed1994

Rethinking "shape space": evidence from simulated docking suggests that steric shape complementarity is not limiting for antibody-antigen recognition and idiotypic interactions.

The concept of "shape space" is based on the assumption that the relevant properties of individual molecules can be adequately specified by a finite list of N parameters; and that cij, the affinity between molecules i and j, can be specified by an equation of the form: cij = f(xi, xj), where xi and xj are N-dimensional vectors representing the absolute positions of molecules i and j in an objective, referential "shape space", and f is an appropriate function. We have performed simulated docking of the combining sites of immunoglobulin molecules, based on their crystallographic structures. The results suggest that shape complementarity cannot account for the specificity of idiotypic interactions, since in the simulations each pair of docked proteins had a buried surface area as great as that occurring in known complexes. It therefore seems likely that the atomic interactions accounting for the specificity of immunoglobulin recognition are highly relational. This casts doubt on the basic assumptions underlying the shape-space concept, at least in the simple form hitherto used in theoretical modelling of the immune system. In order to be realistic, the dimensionality N would have to be high (more than 20), and the function f would be irregular and discontinuous. Alternatively, if the equation cij = f(xi, xj) is interpreted as a purely formal construction in an abstract "inversion space", its validity is entirely relative to the empirical affinity matrix on which the construction is based. We conclude that at present there is no sure way of adequately characterizing the internal structure of idiotypic affinity matrices; and that models of the immune system should therefore aim at being generic and robust with respect to the structure of the idiotypic affinity matrices of unselected immunoglobulins.

Algorithms↗
PubMed1994

The effects of thalidomide treatment on autoimmune-prone NZB and MRL mice are consistent with stimulation of the central immune system.

We describe here some immunomodulatory effects of thalidomide on autoimmune-prone mice. The highly increased synthesis of splenic IgM in NZB mice, of splenic and lymph node IgG of different subclasses in MRL/n mice, and of splenic and lymph node IgG1 in MRL/lpr mice was markedly inhibited by thalidomide treatment. After a single treatment with 3 mg of thalidomide, the following changes were observed in NZB mice: (i) an initial decrease in the numbers of large CD5+ microhigh, and in the numbers of total CD5+ micro-, CD5- microhigh, CD5+ microhigh lymphocyte populations of the pleural cavity followed by a late increase in the numbers of large cells of the three cell populations; (ii) a consistent increase in the numbers of a CD5low microlow pleural lymphoid population; (iii) a consistent reduction in the numbers of splenic large CD5+ B cells and an oscillatory increase in the number of cells with CD5- phenotype; (iv) a late reduction in the numbers of splenic total CD5+ B cells. These results are consistent with the notion that thalidomide controls a disease-associated expansion of B cells in autoimmune prone mouse strains through a stimulatory effect of the drug on the immune system.

Animals↗
PubMed1987

Cell proliferation in synovial membrane of young mice.

The labelling index (LI) of the synoviocytes of the lining-layer cells and of the underlying connective-tissue cells was determined in the synovial membrane of 5-, 10-, 21-, 30-, and 55 day-old mice, following a pulse labelling with [3H]-thymidine. Both the synoviocytes and underlying connective-tissue cells incorporated [3H]-thymidine within 1 h after injection. No significant difference was observed between the LI of these two regions of the synovial membrane. The results indicate that synoviocytes are capable of cell division even in non-pathological conditions.

Animals↗
PubMed1981

Comparative morphologic and histochemical studies on the collagen of vertebrate arteries.

Arteries of representative species from the main vertebrate classes were studied by a method that quantitates collagen-proteoglycans interaction, by the histochemical Picrosirius polarization method and by electron microscopy. The collagen of the adventitia presents features which are characteristic of collagen type I. The collagen in the tunica media revealed histochemical and ultrastructural aspects which are typical of collagen type III. As these results were consistently observed in all species studied, they suggest the presence of a general structural pattern of collagen distribution in vertebrate arteries.

Animals↗